Repeated exposure to cocaine produces persistent adaptations in the brain resulting in an enhanced response to subsequent exposure to psychostimulants, opioids or stress. These include altered supraspinal activation patterns in numerous brain regions. For example, relative to controls, long-term cocaine abusers exhibit lower regional cerebral blood flow (rCBF), glucose utilization, and fMRI bold signaling in limbic regions such as the basal ganglia and frontal cortex and these alterations persist even after long periods of abstinence. However, it is not clear whether these differences in functional activation in the brain are a consequence of drug use or precede drug use and may underly a predisposition to drug addiction (DA). Noxious stimulation also increases neuronal activity in limbic regions and these effects are modulated by opioids in humans. In animals, neuroimaging studies have identified activation of similar brain regions following formalin injection or chronic constriction nerve injury (CCI). For example, twelve weeks following CCI, animals in chronic pain (CP) show a progressive increase in activation in multiple limbic regions, including the cingulate cortex, amygdala, periaqueductal grey and hypothalamic nuclei and limbic regions identified in DA. Unfortunately, no study has looked specifically for overlapping neural circuits in both DA and CP animals. Accordingly, we propose to identify the shared and unique supraspinal mechanisms involved in DA and CP animals and evaluate the effect of an analgesic treatment on these brain systems. First, we will characterize cognitive behaviors in DA and CP animals, coupled with (1) a neuroimaging technique for assessing localized changes in cerebral blood flow in an awake, freely moving animal and (2) receptor autoradioaugraphy to identify changes in dopamine and opioid receptor binding. Second, we will determine the effect of morphine administration on these systems. Specifically, we will identify changes in the activation within limbic regions involved in drug addiction and nociceptive processing. Results from this study will provide important insights into the CNS consequences and neural mechanisms of drug addiction and chronic pain that will lead to the development of new therapies for better management and treatment. PUBLIC HEALTH RELEVANCE: Drug addiction and chronic pain represent two major problems for our society. Both lead to loss of worker productivity and destruction of family and social ties, to name a few. Results from this study will provide important insights into the CNS consequences and neural mechanisms of drug addiction and chronic pain that will lead to the development of new therapies for better management and treatment of these disorders.